C2′-C11′ bond as an unsaturated precursor eliminated
problematic retro-aldol-type fragmentation of advanced
intermediates saturated at C2′-C11′ and delayed introduction
of the C2′ stereocenter.6 Our strategy called for late-stage
introduction of the sensitive spiro-epoxypyranose functional-
ity and allowed for installation of the alkyl residues at C2′,
C8′, and C5 by means amenable to future derivatization.
The requisite aryl electrophile (4) was prepared efficiently
from known triol 6 (Scheme 1).7 While exposure of 6 to
Scheme 2
Scheme 1
of (E)-2-bromo-2-pentenal9 and acetaldehyde furnished, after
basic workup, diol 13 as a single diastereomeric product in
excellent yield. Analogy to previous work suggests that the
high degree of stereo-induction arises from an organized
eight-membered ring chelate (12).10 Protection of 13 as the
corresponding acetonide furnished 5.11
Tandem aldol-Evans-Tishchenko-type additions catalyzed
by divalent and/or trivalent samarium species have been
previously studied,12 and variants catalyzed by other metals
are also known.13 However, the smooth condensation of two
different aldehydes via sequential addition greatly enhances
the scope of this samarium-mediated transformation.
standard bromination conditions led invariably to over-
halogenated species, iodination at the more activated position
proceeded cleanly to 7. Selective benzylation of the phenolic
hydroxyls and silylation of the benzylic alcohol afforded 8
(82% yield, two steps). Stille cross-coupling with (tributyl)-
isobutenylstannane in the presence of catalytic palladium-
(II) furnished 9. Finally, two-step adjustment of the ester
oxidation state gave 4.
Construction of the carbohydrate precursor began with
known vinyl iodide 108, which was elaborated to R-bromo
ketone 11 via the protection, acylation, R-bromination
sequence illustrated in Scheme 2. Formation of the corre-
sponding samarium enolate by treatment of 11 with 2 equiv
of samarium iodide in THF followed by sequential addition
Metal-halogen exchange of vinyl bromide 5 with t-
butyllithium at -78 °C in diethyl ether followed by rapid
addition of a chilled solution of 4 in pentane gave a mixture
of diastereomeric alcohols that were simultaneously oxidized
by Dess-Martin periodinane. Subsequent bis-desilylation
cleanly afforded 14 (Scheme 3). Initial plans called for the
bis-allylic oxidation of 14 and subsequent acetal removal to
afford compounds similar to 17. We anticipated that epoxi-
dation of 17 would be axially directed by the resident
hydroxyl.14 Unfortunately, attempted cyclization of the
requisite bis-aldehyde proved to be frustrating, with apparent
scrambling of the C6′-C8′ olefin geometry and dehydration
always predominating. Fortunately, installation of the epoxide
prior to cyclization effectively eliminated these problems.
(4) Recently, luminacin C2 was isolated in a screen for Src kinase
inhibitors. In vitro experiments suggest that it elicits some of its biological
effects via disruption of SH3-mediated association of any number of
intracellular proteins with Src. See: (a) Sharma, S.; Oneyama, C.;
Yamashita, Y.; Nakano, H.; Sugawara, K.; Hamada, M.; Kosaka, N.;
Tamaoki, T. Oncogene 2001, 20, 2068-2079. (b) Oneyama, C.; Nakano,
H.; Sharma, S. Oncogene 2002, 21, 2037-2050.
(5) Tatsuta and co-workers have recently reported synthetic access to
luminacin C1 (1) and C2 (2). Beginning from L-glucal, their strategy
involves 36 linear steps (43 steps total) and has served to establish both
the relative and absolute stereochemistry for this class of natural products:
Tatsuta, K.; Nakano, S.; Narazaki, F.; Nakamura, Y. Tetrahedron Lett. 2001,
42, 7625-7628.
Although highly diastereoselective epoxidations of primary
allylic alcohols have been observed,15 a model for the
observed diastereoselectivity has not been forthcoming. A
careful screening of a variety of epoxidation conditions in
the present case revealed that VO(acac)2/TBHP afforded 15
(8) Rossi, R.; Carpita, A.; Cossi, P. Synth. Comm. 1993, 23(2), 143-
152.
(9) Lu¨tjens, H.; Knochel, P. Tetrahedron Lett. 1994, 5(7), 1161-1162.
(10) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-
6449.
(6) The relative configuration of this position remained ambiguous prior
to the work of Tatsuta (ref 5).
(7) Saimoto, H.; Yoshida, K.; Murakomi, T.; Marimoto, M.; Sashiwa,
H.; Shigemosa, Y. J. Org. Chem. 1996, 61, 6768-6769
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Org. Lett., Vol. 4, No. 18, 2002